Nine separate projects related to outcomes of patients with rheumatic diseases are included in this report. The first project, Genetic determinants of ankylosing spondylitis severity, is a prospective observational study of 1200 subjects with ankylosing spondylitis (AS) that seeks to identify genetic determinants of AS susceptibility and severity. This project will test genotype-phenotype correlations in a large sample. Over 1200 subjects have been enrolled at five centers including the NIH Clinical Center, and genetic testing and data analysis are underway. Radiographic data have been analyzed on 801 patients. Findings include 26 new genes associated with susceptibility to AS, gene-gene interaction between HLA-B27 and ERAP1 in risk of AS, impact of hip arthritis on physical functioning, lessening of association between radiographic damage and functional impairment with more prolonged AS, added value of using the Health Assessment Questionnaire to measure function in patients with peripheral joint arthritis, and association of ESR and CRP with axial impairments. Collaborators include Drs. J. Reveille, M. Brown, M. Weisman, J. Davis, T. Learch, and J. Malley. Ongoing work will test associations between several candidate genes involved in bone formation and regulation and the extent of radiographic damage. The second project, Progression of spinal fusion in ankylosing spondylitis, is a developmental study to test a measure of spinal fusion in AS based on quantification of calcification of the lumbar intervertebral discs by computed tomography. Thirty-eight subjects have been enrolled, and 33 have completed follow-up scans at 1 and 2 years. Nine subjects have completed studies testing the short-term reliability of measurements. Computerized semi-automatic algorithms for measuring syndesmophyte volume and height have been optimized to maximize reliability. Based on the three-dimensional information provided by these scans, we have discovered that syndesmophytes are non-randomly distributed around the vertebral rim, with preferential formation at the posteriolateral areas. This localization coincides with areas of high mechanical stress and suggests that biomechanics are likely under-recognized factors in syndesmophyte development. We have also developed this method to measure vertebral body height and disk height, which may be useful for precise measurement of vertebral fractures and disk disease. Collaborators on this project are Drs. J. Flynn, L. Yao, Y. Yao, and S. Tan. The third project, Clinically important changes in rheumatoid arthritis, is a prospective observational study of clinically important changes in rheumatoid arthritis (RA) activity. Current criteria for improvement in RA have not emphasized the patients perspective. The goals of this project are to identify benchmarks of important improvement in pain, functioning, and global arthritis status in RA based on the self-assessment by patients of changes in their symptoms. A future goal is to examine the measurement properties of preference measures. To date, 262 patients have been enrolled, and data collection completed on 250 patients. Results indicate patients are consistent in the degree of improvement necessary to be appreciated as an important change, and criteria for improvement have been determined for pain, physical functioning, patient global assessment, and four composite measures of RA activity. We also determined that clinical trial response criteria, such as the ACR20, are quite sensitive, but not specific, measures of improvement. The fourth project, Measurement of physical functioning, uses secondary analysis of clinical trial and observational data to understand which aspects of functioning are being measured in commonly used self-report instruments. We have found that performance measures are neither sensitive nor specific indicators of self-reported functional limitations. We have also found that, contrary to much previous literature, women and men have similar levels of self-reported functional limitations. In addition, we found no racial/ethnic differences in functional limitations after adjustment for measures of disease burden, although large differences by socioeconomic status remained despite adjustment for disease burden. The fifth project, Outcomes in patients with rheumatoid arthritis, uses secondary data to examine risks of mortality, malignancy and cardiovascular disease between patients with RA and those without RA. We have found the perioperative risk of cardiovascular events and mortality not to be increased among persons with rheumatoid arthritis. We are planning a study of trends in risk of colorectal cancer and lymphoma in patients with rheumatoid arthritis, which may vary with changes in the treatments used over time. The sixth project, Treatment-related outcomes in rheumatoid arthritis, uses primary data to examine if particular disease-modifying medications are associated with higher- or lower-than- expected risks of mortality, using advanced statistical methods to account for differential prescribing of more serious medications to sicker patients. We have found that methotrexate is associated with a substantial survival benefit, not attributable to channeling or selective medication use. We also found that low-dose prednisone use was associated with higher risk of mortality, but that this risk was attenuated by concomitant use of disease-modifying medications (methotrexate or sulfasalazine). We are also examining if differential access by patients of higher socioeconomic status to more effective anti-rheumatic medications over the past 25 years has resulted in the widening of socioeconomic disparity in health over time. The goals of the seventh project, Clinical epidemiology of systemic lupus erythematosus, are to investigate health disparities among patients with SLE, and to identify clinical features and health care practices that are associated with health outcomes. We have completed a systematic literature review of risk of end-stage renal disease in patients with lupus nephritis, identifying 161 papers that report these risks. We are now completing a Bayesian meta-analysis of these data to estimate risks of end-stage renal disease by treatment era and world geographic region. The goal of the eighth project, Outcomes in Orthopedics, is to investigate associations between processes and outcomes of orthopedic care. Initial studies have focused on time trends in the incidence of subtrochanteric fractures, using secondary data. Increases in incidence over time in the U.S. have paralleled increased use of bisphosphonate. Also the risk of atypical hip fractures was associated with degree of compliance with bisphosphonate treatment among Medicare beneficiaries. We conducted an observational study examining the association between chronic bisphosphonate use and subtrochanteric beaking, the radiographic precursor of subtrochanteric fracture. We found no difference in subtrochanteric beaking and chronic bisphosphonate use, indicating that this bone change is not an inevitable consequence of treatment. We have also examined differences in outcomes in fracture care related to use of either nails or plates, and have identified perioperative bleeding as a risk for operative site infection. The goal of the ninth project is to test whether patients with RA in clinical remission can safely be withdrawn from treatment with tumor necrosis factor-alpha inhibitors without having relapse of their arthritis. We have initiated a multicenter double-blind placebo-controlled withdrawal trial to test this hypothesis in 300 patients with RA in remission. This study will also provide data on clinical, imaging (joint ultrasound and magnetic resonance imaging), and immunological predictors of relapse.